Agents for the treatment of lower abdominal disorders

ABSTRACT

The invention relates to the use of pantoprazole in the treatment of lower abdominal disorders.

TECHNICAL FIELD

The invention relates to the use of compounds from the class consistingof the add secretion inhibitors for the treatment of lower abdominaldisorders.

PRIOR ART

A whole series of compounds are known from the prior art which inhibitgastric acid secretion by blocking the proton pump and which havetherefore also been designated as proton pump inhibitors (PPI). Thesecompounds are suitable for the treatment of gastric and upper abdominalintestinal disorders and accordingly some of them have been approved byhealth authorities. In international Patent Application WO-A-03053221,an invention is described which provides methods of treating andpreventing asthma, laryngitis, symptomatic gastroesophageal refluxdisease, pregnancy-induced gastroesophageal reflux disease, noncardiacchest pains, coughing, apnea, dyspepsia, inflammatory bowel disease,irritable bowel syndrome, gastritis, stress ulcers, bleeding pepticulcers, acute gastrointestinal bleeding, infectious enteritis,collagenous colitis, lymphocytic colitis, chronic diarrhea inimmunocompromised patients, esophageal ulcers in immunocompromisedpatients, idiopathic gastric acid hypersecretion, gastroparesis,gastrointestinal motility disorders, Zollinger-Ellison syndrome, shortbowel syndrome, emesis, regurgitation, early satiety, chronic sorethroat, abdominal pain, abdominal bloating, nausea, sour stomach,diarrhea, constipation, bacterial infections, refractory ulcers,gastrointestinal disorders induced by NSAIDs, Barrett's esophagus,gastrointestinal disorders caused by steroids, gastrointestinaldisorders induced by cholinergic compounds, and fungal or viral-inducedulcers in the gastrointestinal tract, by administering a therapeuticallyeffective amount of at least one proton pump inhibitor to a patient inneed thereof. The invention described in intentional Patent ApplicationWO-A-03053221 also provides on demand relief of symptoms associated withgastroesophageal reflux disease (GERD), and provides relief fromsymptoms caused by the consumption of excessive amounts of food and/oralcohol by administering a therapeutically effective amount of at leastone proton pump inhibitor to a patent in need thereof. The inventiondescribed in intentional Patent Application WO-A-03053221 also providesmethods for treating parasitic infections, such as malaria, byadministering a therapeutically effective amount of at least one protonpump inhibitor to a patient in need thereof. —Chinese Patent Application1369491 relates to the salts of the levo (−) and dextro (+) enantiomersof the peptic ulcer resistant medicine(±)5-difluoromethoxy-[[3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole,i.e. to the potassium (or sodium, or magnesium, or calcium, or zinc)salt of S-(−)-Pantoprazole (or R-(+)-Pantoprazole). —In U.S. Pat. No.6,156,771, a method of alleviating a lower GI symptom in a human patientafflicted with a lower GI disorder and a method of treating a humanpatient afflicted with a lower GI disorder, including, for example, apatent afflicted with irritable bowel syndrome or a patient afflictedwith functional diarrhea, are provided. Each of these methods comprisesinhibiting gastric secretion by the patient, such as by administering tothe patient a pharmaceutical preparation comprising an effective amountof an inhibitor of gastric secretion, such as a proton pump inhibitor.

DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that the proton pump inhibitors,whose original field of use is the treatment of gastric and upperabdominal intestinal disorders, are particularly suitable for thetreatment of lower abdominal disorders.

The invention thus relates in a first aspect to the use of proton pumpinhibitors in the treatment of lower abdominal disorders.

Proton pump inhibitors are designated as those substances, which inhibitgastric acid secretion by blocking the proton pump, i.e. substanceswhich bind covalently to the H⁺/K⁺-ATPase, the enzyme responsible forgastric add secretion. These include in particular active compoundshaving a 2-[(2-pyridinyl)methylsulphinyl-1H-benzimidazole skeleton orrelated skeletons, where these skeletons may be substituted in variousdifferent ways. The term “proton pump inhibitor” according to theinvention comprises not only the active compounds as such, but alsotheir pharmacologically acceptable salts, solvates (in particularhydrates), etc.

Examples of proton pump inhibitors which may be mentioned are thosedescribed and claimed in the patent applications and patents below:DE-A-3531487, EP-A-0 005 129, EP-A-0 124 495, EP-A-0 166 287, EP-A 0 174726, EP-A-0 184 322, EP-A-0 254 588, EP-A-0 261 478, EP-A-0 268 956,EP-A-0 434 999 and WO-A-9523149. Examples which may be mentioned hereare the compounds2-[2-(N-isobutyl-N-methylamino)benzylsulphinyl]benzimidazole (INN:leminoprazole),2-(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylsulphinyl)-1H-benzimidazole(INN: nepaprazole),2-(4-methoxy-3-methylpyridin-2-ylmethylsulphinyl)5-pyrrol-1-yl-1H-benzimidazole(IY-81149),5-methoxy-2-[(4-meth-oxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-imidazo[4,5-b]pyridine(tenatoprazole), especially5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: omeprazole),5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole(INN: esomeprazole),2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimi-dazole(INN: lansoprazole) and2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulphinyl}-1H-benzimidazole(INN: rabeprazole) and in particular5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: pantoprazole) and(−)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole[INN: (−)-pantoprazole].

The proton pump inhibitors are present as such or in the form of theirsalts with bases. Examples of salts with bases which may be mentionedare sodium, potassium, magnesium or calcium salts. If the proton pumpinhibitors or their salts are isolated in crystalline form, the crystalsmay contain variable amounts of solvent. Correspondingly, according tothe invention, the term “proton pump inhibitor” also includes allsolvates, in particular all hydrates, of the proton pump inhibitors andtheir salts. Particularly preferred salts or hydrates of proton pumpinhibitors, which may be mentioned are pantoprazole-sodium sesquihydrate(=pantoprazole-sodium×1.5 H₂O), (−)-pantoprazole-sodium sesquihydrate,pantoprazole-magnesium dihydrate, omeprazole-magnesium,omeprazole-magnesium tetrahydrate, esomeprazole-magnesium andesomeprazole-magnesium tetrahydrate.

Lower abdominal disorders to be treated, which may be mentioned inparticular are the irritable bowel syndrome (IBS), lower abdominalpain/discomfort (particularly symptomatology), inflammatory boweldiseases such as Colitis ulcerosa (ulcerative colitis) and Morbus Crohn(Crohn's disease, regional enteritis, enterocolitis, ileitis, terminalileitis) and menstrual symptoms.

The invention relates in a further aspect to the use of proton pumpinhibitors for the treatment of patients who are suffering from a lowerabdominal disorder.

The invention further relates to a method for the treatment of lowerabdominal disorders, which consists in administering to a patient whoneeds such a treatment an effective amount of a proton pump inhibitor.

The invention further relates to the use of proton pump inhibitors forthe production of medicaments for the treatment of lower abdominaldisorders.

The invention further relates to a pharmaceutical preparation for thetreatment of lower abdominal disorders, which contains a proton pumpinhibitor as active compound.

The invention further relates to a ready-to-use medicament, comprising aproton pump inhibitor as active compound, which contains a reference tothe fact that this ready-to-use medicament can be employed for thetreatment of lower abdominal disorders.

in particular, it has been found that the proton pump inhibitorpantoprazole, whose original field of use is the treatment of gastricand upper abdominal intestinal disorders, is—due to its long duration ofaction—particularly suitable for the treatment of lower abdominaldisorders.

The invention thus relates in a preferred aspect to the use ofpantoprazole in the treatment of lower abdominal disorders.

According to the invention, “pantoprazole” comprises not only the activecompound as such, but also its enantiomers, i.e. (R)- and(S)-pantoprazole, as well as pharmacologically acceptable salts,solvates (in particular hydrates), etc. of pantoprazole,(R)-pantoprazole and (S)-pantoprazole.

Examples of pharmacologically acceptable salts, which may be mentioned,are sodium, potassium, magnesium or calcium salts. If pantoprazole orits salts is isolated in crystalline form, the crystals may containvariable amounts of solvent.

Particularly preferred salts or hydrates of pantoprazole which may bementioned are pantoprazole-sodium sesquihydrate(=pantoprazole-sodium×1.5 H₂O), (S)-pantoprazole-sodium sesquihydrate,pantoprazole-magnesium dihydrate and (S)-pantoprazole-magnesiumdihydrate.

The invention relates in a preferred aspect to the use of pantoprazolefor the treatment of patients who are suffering from a lower abdominaldisorder.

The invention further particularity relates to a method for thetreatment of lower abdominal disorders, which consists in administeringto a patient who needs such a treatment an effective amount ofpanto-prazole.

The invention further particularly relates to the use of pantoprazolefor the production of medicaments for the treatment of lower abdominaldisorders.

The invention further particularly relates to a pharmaceuticalpreparation for the treatment of lower abdominal disorders, whichcontains pantoprazole as active compound.

The invention further particularly relates to a ready-to-use medicament,comprising pantoprazole as active compound, which contains a referenceto the fact that this ready-to-use medicament can be employed for thetreatment of lower abdominal disorders.

Commercial Utility

According to the invention, the proton pump inhibitors, in particularpantoprazole, are employed for the treatment of lower abdominaldisorders in the form of ready-to-use medicaments. These medicaments areprepared by methods known per se and familiar to the person skilled inthe art. As medicaments, the proton pump inhibitors are either used hereas such, or preferably in combination with suitable pharmaceuticalexcipients or vehicles in the form of tablets, coated tablets, capsules,suppositories, patches (e.g. as TTS), emulsions, suspensions orsolutions, the active compound content advantageously being between 0.1and 95% and it being possible by means of the appropriate choice of theexcipients and vehicles to achieve a pharmaceutical administration formadapted exactly to the active compound and/or to the desired onset ofaction and/or to the duration of action (e.g. a sustained release formor an enteric form).

The person skilled in the art is familiar on the basis of his/her expertknowledge with which excipients or vehicles are suitable for the desiredpharmaceutical formulations. Besides solvents, gel-forming agents,suppository bases, tablet excipients and other active compound carriers,it is possible to use, for example, antoxidants, dispersants,emulsifiers, antifoams, taste corrigents, preservatives, solubilizers,colorants or, in particular, permeation promoters and complexing agents(e.g. cyclodextrins).

The active compounds can be administered orally, parenterally orpercutaneously.

in general, it has proved advantageous in human medicine to administerthe proton pump inhibitor in a daily dose of, in particular, 0.1 to 1.5mg/kg of body weight, if appropriate in the form of a number of,preferably 1 to 2, individual doses to achieve the desired result in thecase of a parenteral treatment, similar or (in particular in the case ofthe intravenous administration of the active compounds) as a rule lowerdosages can be used. The determination of the optimal dosage and mannerof administration of the active compounds necessary in each case can becarried out easily by any person skilled in the art on the basis ofhis/her expert knowledge.

The invention further relates to a pharmaceutical preparation for thetreatment of lower abdominal disorders, which in an individual dose(tablet, capsule, etc.) contains a proton pump inhibitor, in particularpantoprazole, as active compound in a dose of between 5 and 100,advantageously between 10 and 60, in particular between 20 and 40 mg.

If the proton pump inhibitors, in particular pantoprazole, are to beemployed for the treatment of lower abdominal disorders, thepharmaceutical preparations can also contain one or morepharmacologically active constituents of other pharmaceutical groups.Examples, which may be mentioned are: tranquilizers (for example fromthe group consisting of the benzodiazepines, e.g. diazepam),spasmolytics (e.g. bietamiverine or camylofine), anticholinergics (e.g.oxyphencyclimine or phencarbamide), local anesthetics (e.g. tetracaineor procaine), and optionally also enzymes, vitamins or amino acids.

The combination of proton pump inhibitors, in particular pantoprazole,with those pharmaceuticals, which are customarily employed for thetreatment of lower abdominal disorders is to be particularly emphasizedin this context Examples, which may be mentioned, are pharmaceuticalsfor the treatment of Morbus crohn and Colitis ulcerosa, such asaminosalicylates (e. g. mesalazine, olsalazine and sulfosalazine),glucocorticoids (e.g. betamethason, budesonide, hydrocortisone acetate,methylprednisolone, prednisolone and prednisone) and immunosuppressiveagents (e. g. azathioprin, cyclosporin, methotrexat and infliximab),pharmaceuticals for the treatment of diarrhoeas (e. g. colestyramine andloperamide) and pharmaceuticals for the treatment of IBS (e. g.tegaserod).

“Combination” within the meaning of the present invention is to beunderstood as meaning that the individual components can be administeredsimultaneously (in the form of a combination medicament—fixedcombination) or more or less simultaneously, respectively in succession(from separate pack units—free combination; directly in succession orelse alternatively at a relatively large time interval) in a mannerwhich is known per se and customary. As an example, one therapeuticagent could be taken in the morning and one later in the day. Or inanother scenario, one therapeutic agent could be taken once daily andthe other once weekly or only once monthly.

Simultaneous administration preferably is accomplished by administeringto the subject in need thereof, for example, a single intravenousinjection/infusion having a fixed ratio of each therapeutic agent. Moreor less simultaneous administration or administration in succession ofeach therapeutic agent can be effected by any appropriate route,inducing, but not limited to, oral mutes, intravenous routes,intramuscular routes, and by Infusion techniques. The therapeutic agentscan be administered by the same route or by different routes. Forexample, a first therapeutic agent of the combination selected may beadministered by intravenous or subcutaneous injection while the othertherapeutic agent of the combination may be administered orally. Thesequence in which the therapeutic agents are administered is notnarrowly critical.

The therapeutic agent(s) according to the invention may be administeredin a variety of forms. These include, for example, liquid, semi-solidand solid dosage forms, such as liquid solutions (e.g., injectable andinfusible solutions), dispersions or suspensions, tablets, pills,powders, liposomes or suppositories. The preferred form depends on theintended mode of administration and therapeutic application.

1. (canceled)
 2. (canceled)
 3. A method of treating a lower abdominaldisorder in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a proton pump inhibitor,or a hydrate, solvate, salt, hydrate of a salt or solvate of a saltthereof.
 4. (canceled)
 5. (canceled)
 6. A ready-to-use medicamentcomprising a proton pump inhibitor as active compound, or a hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof, and areference to the fact that it can be employed for the treatment of lowerabdominal disorders.
 7. A method according to claim 3, wherein saidproton pump inhibitor is a compound selected from the group consistingof5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl-sulphinyl)-1H-benzimidazole(INN: omeprazole),5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole(INN: esomeprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: lansoprazole),2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulphinyl}-1H-benzimidazole(INN: rabeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: pantoprazole),(−)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole[INN: (−)-pantoprazole] and the hydrates, solvates, salts, hydrates ofthe salts and solvates of the salts thereof.
 8. The method according toclaim 7, wherein said proton pump inhibitor is pantoprazole or apharmacologically acceptable hydrate, solvate, salt, hydrate of a saltor solvate of a salt thereof.
 9. The method according to claim 7,wherein said proton pump inhibitor is racemic pantoprazole or apharmacologically acceptable hydrate, solvate, salt, hydrate of a saltor solvate of a salt thereof.
 10. The method according to claim 7,wherein said proton pump inhibitor is (S)-pantoprazole or apharmacologically acceptable hydrate, solvate, salt, hydrate of a saltor solvate of a salt thereof.
 11. The method according to claim 7,wherein said proton pump inhibitor is pantoprazole-sodium or a hydratethereof.
 12. The method according to claim 7, wherein said proton pumpinhibitor is pantoprazole-magnesium or a hydrate thereof.
 13. The methodaccording to claim 7, wherein said proton pump inhibitor is(S)-pantoprazole-magnesium or a hydrate thereof.
 14. The methodaccording to claim 3, wherein said lower abdominal disorder is selectedfrom the group consisting of irritable bowel syndrome (IBS), lowerabdominal pain/discomfort, symptomatology inflammatory bowel disease,(ulcerative colitis,) Crohn's disease, regional enteritis,enterocolitis, ileitis, terminal ileitis, and menstrual symptoms. 15.(canceled)
 16. A method of treating a lower abdominal disorder in apatient comprising administering to a patient in need thereof atherapeutically effective amount of pantoprazole, or a hydrate, solvate,salt, hydrate of a salt or solvate of a salt thereof.
 17. (canceled) 18.(canceled)
 19. A ready-to-use medicament comprising pantoprazole asactive compound, or a hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof, and a reference to the fact that it can beemployed for the treatment of lower abdominal disorders.
 20. Aready-to-use medicament for the treatment of lower abdominal disorderscomprising pantoprazole, or a hydrate, solvate, salt, hydrate of a saltor solvate of a salt thereof, as one active compound and a second activecompound selected from aminosalicylates glucocorticoids,immunosuppressive agents pharmaceuticals for the treatment of diarrhoeasand pharmaceuticals for the treatment of IBS.
 21. A ready-to-usemedicament according to claim 19, wherein the lower abdominal disorderis selected from the group consisting of irritable bowel syndrome (IBS),lower abdominal pain/discomfort, symptomatology inflammatory boweldisease, ulcerative colitis, Crohn's disease, regional enteritis,enterocolitis, ileitis, terminal ileitis, and menstrual symptoms. 22.(canceled)
 23. A ready-to-use medicament according to claim 6, whereinsaid proton pump inhibitor is a compound selected from the groupconsisting of5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: omeprazole),5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole(INN: esomeprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: lansoprazole),2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulphinyl}-1H-benzimidazole(INN: rabeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole(INN: pantoprazole),(−)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole[INN: (−)-pantoprazole] and the hydrates, solvates, salts, hydrates ofthe salts and solvates of the salts thereof.
 24. The ready-to-usemedicament according to claim 19, wherein said proton pump inhibitor isracemic pantoprazole or a pharmacologically acceptable hydrate, solvate,salt, hydrate of a salt or solvate of a salt thereof.
 25. Theready-to-use medicament according to claim 19, wherein said proton pumpinhibitor is (S)-pantoprazole or a pharmacologically acceptable hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof.
 26. Theready-to-use medicament according to claim 19, wherein said proton pumpinhibitor is pantoprazole-sodium or a hydrate thereof.
 27. Theready-to-use medicament according to claim 19, wherein said proton pumpinhibitor is pantoprazole-magnesium or a hydrate thereof.
 28. Theready-to-use medicament according to claim 19, wherein said proton pumpinhibitor is (S)-pantoprazole-magnesium or a hydrate thereof.
 29. Theready-to-use medicament according to claim 6, wherein said lowerabdominal disorder is selected from the group consisting of irritablebowel syndrome (IBS), lower abdominal pain/discomfort, symptomatologyinflammatory bowel disease, ulcerative colitis, Crohn's disease,regional enteritis, enterocolitis, ileitis, terminal ileitis, andmenstrual symptoms.
 30. The ready-to-use medicament according to claim20, wherein the second active compound is selected from the groupconsisting of mesalazine, olsalazine, sulfosalazine, betamethason,budesonide, hydrocortisone acetate, methylprednisolone, prednisolone,prednisone, azathioprin, cyclosporin, methotrexat, infliximab,colestyramine, loperamide and tegaserod.